Heating Device for Testing a Biological Sample

ABSTRACT

A heating device for testing a biological sample is disclosed. The heating device can include a heat source operable to generate heat. In addition, the heating device can include a controller in communication with the heat source and operable to control heat generation by the heat source to heat a biological sample at less than or equal to about 2 degrees C./s. Furthermore, a heating device for testing a biological sample is disclosed that can include a heat source operable to generate heat to heat a biological sample. The biological sample can be at least partially contained within a removable enclosure distinct from the heating device. Additionally, the heating device can include an enclosure interface associated with the heat source. The enclosure interface can be configured to interface with the enclosure such that heat is transferred from the heat source to the enclosure by conduction.

RELATED APPLICATION

This application claims the benefit of U.S. Provisional PatentApplication Ser. No. 63/138,310 filed Jan. 15, 2021, U.S. ProvisionalPatent Application Ser. No. 63/138,312 filed Jan. 15, 2021, U.S.Provisional Patent Application Ser. No. 63/138,314 filed Jan. 15, 2021,U.S. Provisional Patent Application Ser. No. 63/138,316 filed Jan. 15,2021, U.S. Provisional Patent Application Ser. No. 63/138,318 filed Jan.15, 2021, U.S. Provisional Patent Application Ser. No. 63/138,320 filedJan. 15, 2021, U.S. Provisional Patent Application Ser. No. 63/138,321filed Jan. 15, 2021, U.S. Provisional Patent Application Ser. No.63/138,323 filed Jan. 15, 2021, U.S. Provisional Patent Application Ser.No. 63/138,337 filed Jan. 15, 2021, U.S. Provisional Patent ApplicationSer. No. 63/138,341 filed Jan. 15, 2021, U.S. Provisional PatentApplication Ser. No. 63/148,527 filed Feb. 11, 2021, the entire contentsof each of which are incorporated herein by reference.

BACKGROUND

In some forms of pathogen testing (e.g., Loop-Mediated IsothermalAmplification (LAMP)), a heating process can be utilized to test abiological sample for the presence of a pathogen (e.g., a viralpathogen, a bacterial pathogen, a fungal pathogen, or a protozoapathogen). Such tests can use a simple visual output test indicator,such as a color change, to identify the presence or absence of apathogen. These tests can be performed with minimal equipment (e.g.,sample collection and preparation tools, a heating device, etc.) andsample preparation and can therefore be accessible for use in point ofcare settings, such as clinics, emergency rooms, and even on a mobilebasis.

BRIEF DESCRIPTION OF THE DRAWINGS

Features and advantages of the invention will be apparent from thedetailed description which follows, taken in conjunction with theaccompanying drawings, which together illustrate, by way of example,features of the invention; and, wherein:

FIG. 1 is a schematic illustration of a biological test system inaccordance with an example of the present disclosure.

FIGS. 2A and 2B are schematic illustrations of a liquid biologicalsample test cartridge in accordance with an example of the presentdisclosure.

FIG. 3A is a top isometric view of a biological test system inaccordance with an example of the present disclosure.

FIG. 3B is a top isometric view of the biological test system of FIG. 3Awith a lid of a heating device in an open configuration, in accordancewith an example of the present disclosure.

FIG. 4 is a schematic illustration of the biological test system ofFIGS. 3A and 3B.

FIG. 5A is a top isometric view of a heating device of the biologicaltest system of FIGS. 3A and 3B, in accordance with an example of thepresent disclosure.

FIG. 5B is a bottom isometric view of the heating device of FIG. 5A, inaccordance with an example of the present disclosure.

FIG. 5C is a top isometric view of the heating device of FIG. 5A with alid in an open configuration, in accordance with an example of thepresent disclosure.

FIG. 6 is a feedback control diagram for controlling heating abiological sample in the biological test system of FIGS. 3A and 3B, inaccordance with an example of the present disclosure.

FIG. 7 illustrates multiple heating devices as in the biological testsystem of FIGS. 3A and 3B coupled to one another, in accordance with anexample of the present disclosure.

FIG. 8A is a top isometric view of a liquid biological sample testcartridge of the biological test system of FIGS. 3A and 3B, inaccordance with an example of the present disclosure.

FIG. 8B is a bottom isometric view of the liquid biological sample testcartridge of FIG. 8A, in accordance with an example of the presentdisclosure.

FIG. 9A is a top isometric view of a tray of the liquid biologicalsample test cartridge of FIGS. 8A and 8B, in accordance with an exampleof the present disclosure.

FIG. 9B is a top isometric view of the tray of FIG. 9A supporting achemical reaction pad, in accordance with an example of the presentdisclosure.

FIG. 9C is a bottom isometric view of the tray of FIG. 9A, in accordancewith an example of the present disclosure.

FIG. 10 is a top isometric view of the tray of FIG. 9A with a chemicalreaction pad cover over the chemical reaction pad, in accordance with anexample of the present disclosure.

FIG. 11A is a top isometric view of the chemical reaction pad cover ofFIG. 10, in accordance with an example of the present disclosure.

FIG. 11B is a bottom isometric view of the chemical reaction pad coverof FIG. 10, in accordance with an example of the present disclosure.

FIG. 12A is a top isometric view of an outer cover of the liquidbiological sample test cartridge of FIGS. 8A and 8B, in accordance withan example of the present disclosure.

FIG. 12B is a bottom isometric view of the outer cover of the liquidbiological sample test cartridge of FIG. 12A, in accordance with anexample of the present disclosure.

FIG. 13A is a top view of the chemical reaction pad of FIG. 9B, inaccordance with an example of the present disclosure.

FIG. 13B is a side view of the chemical reaction pad of FIG. 13A, inaccordance with an example of the present disclosure.

FIG. 14A is a top view of a chemical reaction pad in accordance with anexample of the present disclosure.

FIG. 14B is a side view of the chemical reaction pad of FIG. 14A, inaccordance with an example of the present disclosure.

FIG. 15 is a top view of a chemical reaction pad in accordance with anexample of the present disclosure.

FIG. 16 is a top view of a chemical reaction pad in accordance with anexample of the present disclosure.

FIG. 17 is a top view of a chemical reaction pad in accordance with anexample of the present disclosure.

FIG. 18 is a top view of a chemical reaction pad in accordance with anexample of the present disclosure.

FIG. 19 is a top view of a chemical reaction pad in accordance with anexample of the present disclosure.

FIG. 20 is a schematic illustration of a chemical reaction pad inaccordance with an example of the present disclosure.

FIGS. 21A-21C capillary channel cross-sectional shapes in accordancewith several examples of the present disclosure.

FIG. 22 illustrates a tray and the chemical reaction pad of the liquidbiological sample test cartridge of FIG. 8A, with the chemical reactionpad cover omitted for clarity.

FIG. 23 illustrates a top view of the liquid biological sample testcartridge of FIG. 8A, showing the chemical reaction pad visible throughthe chemical reaction pad cover and the outer cover.

FIG. 24 is a top isometric view of a liquid biological sample testcartridge in accordance with an example of the present disclosure.

FIG. 25 is a schematic illustration of a liquid biological sample testkit in accordance with an example of the present disclosure.

Reference will now be made to the exemplary embodiments illustrated, andspecific language will be used herein to describe the same. It willnevertheless be understood that no limitation of the scope of theinvention is thereby intended.

DETAILED DESCRIPTION

As used herein, the term “substantially” refers to the complete ornearly complete extent or degree of an action, characteristic, property,state, structure, item, or result. For example, an object that is“substantially” enclosed would mean that the object is either completelyenclosed or nearly completely enclosed. The exact allowable degree ofdeviation from absolute completeness may in some cases depend on thespecific context. However, generally speaking the nearness of completionwill be so as to have the same overall result as if absolute and totalcompletion were obtained. The use of “substantially” is equallyapplicable when used in a negative connotation to refer to the completeor near complete lack of an action, characteristic, property, state,structure, item, or result.

As used herein, “adjacent” refers to the proximity of two structures orelements. Particularly, elements that are identified as being “adjacent”may be either abutting or connected. Such elements may also be near orclose to each other without necessarily contacting each other. The exactdegree of proximity may in some cases depend on the specific context.

An initial overview of the inventive concepts are provided below andthen specific examples are described in further detail later. Thisinitial summary is intended to aid readers in understanding the examplesmore quickly, but is not intended to identify key features or essentialfeatures of the examples, nor is it intended to limit the scope of theclaimed subject matter.

In one aspect, a heating device for testing a biological sample isdisclosed that can include a heat source operable to generate heat. Inaddition, the heating device can include a controller in communicationwith the heat source and operable to control heat generation by the heatsource to heat a biological sample at less than or equal to about 2degrees C./s.

In one aspect, a heating device for testing a biological sample isdisclosed that can include a heat source operable to generate heat toheat a biological sample. The biological sample can be at leastpartially contained within a removable enclosure distinct from theheating device. Additionally, the heating device can include anenclosure interface associated with the heat source. The enclosureinterface can be configured to interface with the enclosure such thatheat is transferred from the heat source to the enclosure by conduction.

To further describe the present technology, examples are now providedwith reference to the figures. With reference to FIG. 1, one embodimentof a biological test system 100 is schematically illustrated. Ingeneral, the biological test system 100 can comprise a biological sample101 and a heating device 102 for testing the biological sample 101. Inone aspect, the biological test system 100 can provide for point-of-care(POC) testing of the biological sample 101 in an in-patient orout-patient hospital setting, a physician office laboratory, a drivethru clinic, a pharmacy, a community care setting, etc. In someexamples, the biological sample 101 can be contained within a suitableenclosure 103, such as that provided by a test cartridge as disclosedherein and discussed in more detail below. The enclosure 103 can serveto provide a suitable test environment for the biological sample 101.

The biological sample 101 can be or include any suitable biologicalmaterial, such as saliva, mucus, blood, urine, feces, etc. The heatingdevice 102 can be utilized in any suitable manner to perform a giventype of test on the biological sample 101. Examples of suitable teststhat may be performed using the biological test system 100 are disclosedin U.S. patent application Ser. No. ______ (TNW Attorney Docket No.3721-20.14629), which is incorporated herein by reference in itsentirety.

In one aspect, Loop-Mediated Isothermal Amplification (LAMP) can beutilized to perform diagnostic identification of target nucleotides thatreside in a pathogen of interest, which may be present in the biologicalsample 101. LAMP is a one-step nucleic acid amplification method tomultiply specific nucleotide sequences. In addition to use of anisothermal heating process, which can be executed by the heating device102, LAMP can use a simple visual output test indicator, such as a colorchange. Reverse-transcription LAMP (RT-LAMP) can be used in order toidentify target nucleotides from RNA, and as such, can be used in adiagnostic capacity to identify the presence or absence of viralpathogens. Thus, in cases where the pathogen is a virus, the LAMPanalysis can be an RT-LAMP analysis. In one aspect, the biologicalsample 101 can be in the presence of one or more reagents including oneor more target primers, DNA polymerase, and a re-solubilization agent.In another aspect, the reagents can form a composition sufficient tocarry out a LAMP reaction.

In one aspect, the target pathogen can comprise a viral pathogen, abacterial pathogen, a fungal pathogen, or a protozoa pathogen. In oneaspect, the target pathogen can comprise a viral pathogen. In oneaspect, the viral pathogen can comprise a dsDNA virus, an ssDNA virus, adsRNA virus, a positive-strand ssRNA virus, a negative-strand ssRNAvirus, an ssRNA-RT virus, or a ds-DNA-RT virus. In one aspect, eachprimer sequence can match a sequence from a viral target comprisingH1N1, H2N2, H3N2, H1N1pdm09, or SARS-CoV-2.

In another aspect, the target nucleotide sequence can be from at leastone of a viral pathogen, a bacterial pathogen, a fungal pathogen, or aprotozoan pathogen. In one aspect, the target nucleotide sequence can befrom a viral pathogen. In one aspect, the viral pathogen can be selectedfrom the group consisting of: Coronoviridae, Orthomyxoviridae,Paramyxoviridae, Picomaviridae, Adenoviridae, and Parvoviridae. Inanother aspect, the viral pathogen can be selected from the groupconsisting of: severe acute respiratory syndrome coronavirus(SARS-CoV-1), severe acute respiratory syndrome coronavirus 2(SARS-CoV-2), Middle East respiratory syndrome (MERS), influenza, andH1N1. In one aspect, the target nucleotide sequence can be from a severeacute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen.

With further reference to FIG. 1, the heating device 102 can include aheat source 110 operable to generate heat. The heat source 110 cancomprise any suitable type of heater or heating element known in theart, such as at least one of a resistance heater (e.g., a polymerthick-film (PTF) heating element), an induction heater, a radiantheater, a convection heater, a chemical heater (e.g., heat produced byan exothermic chemical reaction), a thermoelectric heater (e.g., aPeltier device or heater), or a heat spreader. In one aspect, the heatsource 110 can be operable to provide uniform heating across thebiological sample 101. In one aspect, the heat source 110 can providefor a heating uniformity within the enclosure 103 that has a variabilityof less than 1 degree C. The spatial variability of the temperaturearound the enclosure 103 should not be greater than about 0.5 degrees C.to avoid interference with a LAMP reaction. In one example, the heatsource 110 can be physically separated from the biological sample 101such that heat is transferred from the heat source to the biologicalsample by at least one of radiation or convection. In one aspect, theheating device 102 can include a chamber 111 configured to receive thebiological sample 101 therein. In this case, the chamber 111 and theheater 110 can form an oven. In some examples, the chamber 111 can bedefined at least in part by a portion of the heat source 110 (e.g.,forming at least a portion of a wall of the chamber 111). In oneexample, the biological sample 101 can be at least partially containedwithin the enclosure 103 (e.g., as provided by a test cartridge). In oneaspect, the heat source 110 can be configured to interface with theenclosure 103 such that heat is transferred from the heat source 110 tothe enclosure 103 by conduction. In another aspect, heat can betransferred from the heat source 110 to the enclosure 103 by at leastone of radiation or convection (e.g., the enclosure 103 or testcartridge is located in an oven or the chamber 111).

In some examples, the heating device 102 can include a controller 112 incommunication with the heat source 110. The controller 112 can beoperable to control heat generation by the heat source 110 to heat thebiological sample 101 at a temperature “ramp rate,” which is an increaseof temperature as a function of time, as opposed to a steady statetemperature that does not change appreciably over time. In one aspect,the controller 112 can be operable to control heat generation by theheat source 110 to heat the biological sample 101 at a ramp rate of lessthan or equal to about 2 degrees C./s. In one aspect, the controller 112can be operable to control heat generation by the heat source 110 toheat the biological sample at a ramp rate from about 0.5-1.5 degreesC./s. In another aspect, the controller 112 can be operable to controlheat generation by the heat source 110 to heat the biological sample ata ramp rate from about 0.8-1.2 degrees C./s. In yet another aspect, thecontroller 112 can be configured to control heat generation by the heatsource 110 to heat the biological sample at a target ramp rate less thanor equal to about 2 degrees C./s (e.g., about 0.1 degrees C./s) ascontrolled by a feedback control loop. For example, the heating device102 can include a thermal sensor 113 in communication with thecontroller 112. The thermal sensor 113 can be operable to sense atemperature associated with the biological sample 101, and thecontroller 112 can control heat generation by the heat source 110 basedon the temperature.

In some examples, an amount of reverse transcriptase can be providedsufficient to facilitate an RT-LAMP reaction. In one example, thereverse transcriptase can be activated at about 55 degrees C. and theDNA polymerase can be activated at about 65 degrees C. In one example,the ramp rate can be raised until the test environment temperature is ina range from about 60 degrees C. to about 67 degrees C. Consequently, aramp rate higher than about 0.2 degrees C./s can interfere with the LAMPreaction. In some examples, when the test environment is increased toabout 55 degrees C. (i.e., the temperature at which the reversetranscriptase can be activated), with a ramp rate of about 0.1 degreesC. from 55 degrees C. to about 65 degrees C., the biological sample testapparatus can provide invalid results. Therefore, the ramp rate shouldbe monitored not just in the testing environment temperature range fromabout 55 degrees C. to about 65 degrees C., but also as the biologicalsample is being heated to about 55 degrees C.

The thermal sensor 113 can be or include any suitable type of sensorknown in the art, such as, broadly speaking, at least one of a contactsensor or a non-contact sensor. In particular, non-limiting examples ofthe thermal sensor 113 can include at least one of an optical thermalsensor, an infrared thermal sensor, a thermocouple, a thermistor, or aresistance temperature detector (RTD). In one example, the heatingdevice 102 can include a thermal sensor 114 in communication with thecontroller 112 that can be operable to sense a temperature associatedwith the heat source 110. In some examples, the thermal sensor 114 canbe used to determine whether a suitable cool-down temperature (e.g., foruser safety) has been reached following completion of a test of thebiological sample 101. The thermal sensor 114 can be of any suitabletype known in the art as discussed above relative to the thermal sensor113.

In one aspect, the heating device 102 can include a timer or clock 115in communication with the controller 112. The timer 115 can be operableto provide time data to the controller 112. The controller 112 cancontrol the heater 110 to provide heat for a predetermined incubationtime period based on data provided by the timer 115 and, in someexamples, data provided by the thermal sensor 113. The timer 115 can beor include any suitable type of timer or clock known in the art toprovide time information or data to the controller 112, such as, broadlyspeaking, at least one of a hardware clock or a software clock.

In one aspect, a testing time can be from about 15 minutes to about 30minutes for a saliva sample. In another aspect, a testing time can befrom about 30 minutes to about 45 minutes for a saliva sample. Inanother aspect, a testing time can be from about 45 minutes to about 60minutes for a saliva sample. In another aspect, a testing time can befrom about 60 minutes to about 90 minutes for a saliva sample. Inanother aspect, a testing time can be from about 20 minutes to about 30minutes for a nasopharyngeal sample. In another aspect, a testing timecan be from about 30 minutes to about 40 minutes for a nasopharyngealsample.

In one aspect, the heat source 110 can be configured to isothermallyheat the enclosure 103 to an internal temperature sufficient to initiateand sustain a LAMP reaction between a LAMP reagent mixture and thebiological sample 101 for a time used to generate a test result via thepH-sensitive dye.

In one aspect, the heat source 110 can be configured to actively and/orpassively cool the enclosure 103. In some examples, the heat source 110can comprise a thermoelectric heater (e.g., a Peltier device or heater),which can also be operable as a cooler (e.g., a heat pump) to activelycool the enclosure 103 and reduce the time needed to cool the enclosure103 sufficient for safe handling.

The controller 112 can have any suitable structure and can include anysuitable component known in the art to perform the function of acontroller as disclosed herein. For example, the controller 112 caninclude any suitable hardware (e.g., a processor 117, computer memory118, etc.) and/or software operable to control operation of the heatsource 110 and/or communicate with and process data from the thermalsensors 113, 114 and/or the timer 115. It should be appreciated by thoseskilled in the art that the controller 112 can include a tangible andnon-transitory computer readable medium comprising one or more computersoftware modules configured to direct one or more processors to performthe method steps and functions/operations described herein.

FIGS. 2A and 2B schematically illustrate an example of a liquidbiological sample test cartridge 204 that can be used with a heatingdevice as disclosed herein to test a biological sample. The cartridge204 can include a tray 220. The cartridge 204 can also include achemical reaction pad 221 supported by the tray 220. The cartridge 204can further include a chemical reaction pad cover 222 disposed over thechemical reaction pad 221. The chemical reaction pad cover 222 can becoupled to the tray 220. The chemical reaction pad cover 222 can have asample opening 223 to facilitate depositing a liquid biological sample201 on the chemical reaction pad 221 (e.g., at a predeterminedlocation). In addition, the cartridge 204 can include an outer cover 224operable to at least partially form an enclosure 203 (FIG. 2B) about thechemical reaction pad 221.

The chemical reaction pad 221 can have any suitable configuration andcomposition of materials, which can be selected based on a type of testto be performed on the biological sample 201. In one aspect, thechemical reaction pad 221 can comprise a “solid phase medium,” whichrefers to a non-liquid medium. In one example, the non-liquid medium canbe a material with a porous surface. In another example, the non-liquidmedium can be a material with a fibrous surface. In yet another example,the non-liquid medium can be paper. A “solid phase medium,” “solid phasebase” “solid phase substrate” “solid phase test substrate” “solid phasetesting substrate,” “solid phase reaction medium” and the like can beused interchangeably herein and refer to a non-liquid medium, device,system, or environment. In some aspects, the non-liquid medium may besubstantially free of liquid or entirely free of liquid. In one example,the non-liquid medium can comprise or be a porous material or a materialwith a porous surface. In another example, the non-liquid medium cancomprise or be a fibrous material or a material with a fibrous surface.In yet another example, the non-liquid medium can be a paper.

There are various materials that the solid-phase reaction medium can becomprise or include. In one aspect, the solid-phase reaction medium cancomprise one or more of glass fiber, nylon, cellulose, polysulfone,polyethersulfone, cellulose acetate, nitrocellulose, hydrophilicpolytetrafluoroethylene (PTFE), the like, or combinations thereof. Inanother aspect, the solid-phase reaction medium can be a cellulose-basedmedium.

In some examples, the chemical reaction pad 221 can include asolid-phase reaction medium in combination with a LAMP reagent mixtureand a pH sensitive dye. In some examples, the chemical reaction pad 221can include a substrate engaging a solid phase reaction medium incombination with a dehydrated loop-mediated isothermal amplification(LAMP) reagent mixture and a dehydrated pH-sensitive dye. In one aspect,the substrate can comprise an optically transparent material. In anotheraspect, the substrate can engage the solid phase reaction medium via anadhesive. In another aspect, the adhesive can be substantially opticallytransparent. In another aspect, an adhesive layer can be disposed on asubstrate, a reaction layer can be disposed on the adhesive layer, and aspreading layer can be disposed on the reaction layer. These and otheraspects of a chemical reaction pad as disclosed herein are discussed inmore detail below.

FIGS. 3A and 3B illustrate a biological test system 300 in accordancewith an example of the present disclosure. A schematic representation ofthe biological test system 300 is shown in FIG. 4. The biological testsystem 300 can include a heating device 302 and a liquid biologicalsample test cartridge 304, which can be configured to contain abiological sample 301 for testing. Various aspects and features of theheating device 302 are shown more particularly in FIGS. 5A-7. Variousaspects and features of the cartridge 304 are shown more particularly inFIGS. 8A-23.

The fully assembled cartridge 304 is shown isolated from the heatingdevice 302 in FIGS. 8A and 8B. In general, as with the cartridge 204 ofFIGS. 2A and 2B, the cartridge 304 can include a tray 320 (FIGS. 9A-10),a chemical reaction pad 321 upon which the biological sample 301 can bedeposited (FIGS. 9B, 13A, and 13B), a chemical reaction pad cover 322(FIGS. 10-11B), and an outer cover 324 (FIGS. 8A, 8B, 12A, and 12B). Theouter cover 324 can be operable to at least partially form an enclosure303 (FIGS. 8A and 8B) about the biological sample 301.

The heating device 302 is shown isolated from the cartridge 304 in FIGS.5A-5C. In general, as with the heating device 102 of FIG. 1, the heatingdevice 302 can include a heat source 310 (FIG. 4) operable to generateheat to heat the biological sample 301. In the case of the heatingdevice 302, the biological sample 301 can be at least partiallycontained within a removable enclosure (e.g., the enclosure 303 providedby the cartridge 304), which is distinct from the heating device 302.The heating device 302 can include an enclosure interface 360 associatedwith the heat source 310. The enclosure interface 360 can be configuredto interface with the enclosure 303 (e.g., the outer cover 324) suchthat heat is transferred from the heat source 310 to the enclosure 303by conduction. An outer surface defining the enclosure 303 (e.g., anouter surface of a bottom wall 355 a of the outer cover 324 shown inFIG. 8B) can be configured to interface with the enclosure interface 360or the heat source 310 (e.g., a heater, a heating element, or relatedstructure, such as a heat spreader) of the heating device 302. In oneaspect, the heat source 310 can be operable to provide uniform heatingacross the biological sample 301, such as by evenly heating the bottomwall 355 a of the outer cover 324 via the enclosure interface 360. Theheat source 310 can comprise any suitable type of heater or heatingelement known in the art, such as at least one of a resistance heater(e.g., a polymer thick-film (PTF) heating element), an induction heater,a radiant heater, a convection heater, a thermoelectric heater (e.g., aPeltier device or heater), or a heat spreader. In some examples, a heatspreader can be separate and distinct from the heat source 310 (e.g., aspatially removed and separate component).

In one aspect, the heat source 310 can be configured to actively and/orpassively cool the enclosure 303 (e.g., the outer cover 324). In someexamples, the heat source 310 can comprise a thermoelectric heater(e.g., a Peltier device or heater), which can also be operable as acooler (e.g., a heat pump) to actively cool the enclosure 303 (e.g., theouter cover 324) and reduce the time needed to cool the enclosure 303sufficient for safe handling.

With reference to FIG. 4, the heating device 302 can include acontroller 312 in communication with the heat source 310. In one aspectthe controller 312 can be operable to control heat generation by theheat source 310 to heat the biological sample at a ramp rate less thanor equal to about 2 degrees C./s. In one aspect, the controller 312 canbe operable to control heat generation by the heat source 310 to heatthe biological sample at a ramp rate from about 0.5-1.5 degrees C./s. Inanother aspect, the controller 312 can be operable to control heatgeneration by the heat source 310 to heat the biological sample at aramp rate from about 0.8-1.2 degrees C./s. In yet another aspect, thecontroller 312 can be configured to control heat generation by the heatsource 310 to heat the biological sample at a target ramp rate less thanor equal to about 2 degrees C./s (e.g., about 0.1 degrees C./s) ascontrolled by a feedback control loop. For example, the heating device302 can include a thermal sensor 313 in communication with thecontroller 312. The thermal sensor 313 can be operable to sense atemperature associated with the biological sample 301, and thecontroller 312 can control heat generation by the heat source 310 basedon the temperature. The temperature associated with the biologicalsample 301 can be a temperature of at least a portion of the enclosure303 (e.g., a surface of the outer cover 324, such as an outer surface ofa top wall 355 b of the outer cover 324).

The thermal sensor 313 can be or include any suitable type of sensorknown in the art, such as, broadly speaking, at least one of a contactsensor or a non-contact sensor. In particular, non-limiting examples ofthe thermal sensor 313 can include at least one of an optical thermalsensor, an infrared thermal sensor, a thermocouple, a thermistor, or aresistance temperature detector (RTD). In one example, the heatingdevice 302 can include a thermal sensor 314 in communication with thecontroller 312 that can be operable to sense a temperature associatedwith the heat source 310. In some examples, the thermal sensor 314 canbe used to determine whether a suitable cool-down temperature (e.g., foruser safety) has been reached following completion of a test of thebiological sample 301. The thermal sensor 314 can be of any suitabletype known in the art as discussed above relative to the thermal sensor313.

One example of a feedback control diagram for controlling heating of thebiological sample 301 is shown in FIG. 6. In this example, thecontroller 312 can comprise a digital PID(proportional-integral-derivative) controller and the sensor 313 cancomprise a non-contact infrared (IR) sensor, although any suitablecontroller and sensor type can be utilized. In FIG. 6, T_(IR) is thetemperature sensed from the IR sensor, which can have a viewing angledirected at a center of the cartridge 304 (e.g., a center of a regionwithin the cartridge where the biological sample 301 is located). Thetemperature of the top side of the cartridge 304 (e.g., the outersurface of the top wall 355 b of the outer cover 324) where the T_(IR)is taken may lag the temperature of the biological sample 301 within thecartridge 304 during heating. This temperature difference is referred toas T_(offset). The offset temperature T_(offset) can be determinedthrough empirical testing and/or thermal modeling to determine thedifference between the IR sensor temperature reading and the actualtemperature of the biological sample or assay. T_(offset) can be appliedto the measured T_(IR) temperature to produce a calculated T_(assay)temperature, which is the temperature of the biological sample 301. ThisT_(assay) temperature is compared to the set point temperature T_(set),which is the target temperature of the biological sample 301 and isselected to control the maximum temperature of the biological sample 301during the test. The error produced by taking the difference betweenT_(assay) and T_(set) is sent to the digital PID controller, whichoutputs a heater control on/off duty cycle. Based on this duty cycle,the heater will produce a corresponding heat which is applied to theenclosure interface 360. The enclosure interface 360 is in contact withthe cartridge 304 (e.g., the outer cover 324), which contains thebiological sample 301. Thus, the cartridge 304 (e.g., the outer surfaceof the top wall 355 b of the outer cover 324) will heat up to atemperature of T_(cart), completing the control loop.

In some examples, a desired temperature ramp rate may not be directlycontrolled by the PID controller. For example, the integral term of thePID controller may be set to keep the PID controller at a relativelyslow speed, which can result in the heater ramping at a slow rate thatfalls within a desired ramp rate range. In some examples, the PIDcontroller can control a desired temperature ramp rate by beingconfigured to control the error term received by the PID controller(i.e., the error produced by taking the difference between T_(assay) andT_(set)) to decrease at a magnitude equal to the desired temperatureincrease ramp rate.

In one aspect, the heating device 302 can include a timer or clock 315in communication with the controller 312. The timer 315 can be operableto provide time data to the controller 312. The timer 315 can be orinclude any suitable type of timer or clock known in the art to providetime information or data to the controller 312, such as, broadlyspeaking, at least one of a hardware clock or a software clock. Thecontroller 312 can control the heater 310 to provide heat for apredetermined incubation time period based on data provided by the timer315 and, in some examples, data provided by the thermal sensor 313. Inone example, once the biological sample 301 reaches the temperature setpoint T_(set), the timer 315 can start and run for a predetermined timeperiod. The timer 315 can control how long the biological sample 301will remain at the set point temperature. In some examples, thecontroller 312 can control the heat source 310 to produce a temperature“spike,” where the temperature of the biological sample 301 is increasedto a predetermined temperature and maintained at that temperature for aperiod of time, as measured by the timer 315. Once this time period haselapsed, the heat source 310 can be turned off and the system 300 can beallowed to cool down until the cartridge 304 is at a safe temperaturefor handling by a user.

The controller 312 can have any suitable structure and can include anysuitable components known in the art to perform the function of acontroller as disclosed herein. For example, the controller 312 caninclude any suitable hardware (e.g., a processor 317, computer memory318, etc.) and/or software operable to control operation of the heatsource 310 and/or communicate with and process data from the thermalsensors 313, 314 and/or the timer 315. It should be appreciated by thoseskilled in the art that the controller 312 can include a tangible andnon-transitory computer readable medium comprising one or more computersoftware modules configured to direct one or more processors to performthe method steps and operations described herein.

In some examples, as illustrated in FIG. 3A, the heating device 302 caninclude a visual indicator 370, such as one or more lights or any othersuitable visual indicator (e.g., LED lights of the same or differentcolors, a display, etc.) to assist the user in operating the heatingdevice 302 and/or to provide information to the user (e.g., indicatetesting progress and/or provide an alert when a test has reachedconclusion, signal an error or other malfunction of the heater, indicatethat a starting temperature has been reached, and any other notificationor information). Alternatively, or in addition, the heating device 302can include a speaker or other sound generation device (not shown) thatcan perform the same functions. In some examples, the heating device 302can include a user interface 371, such as a button, a knob, a lever, atouch pad, a touch screen display, or other suitable user interfaceknown in the art, to provide the user with a certain degree of controlover operation of the heating device 302 (e.g., power on/off, begin atest, access/select device control/configuration menu items, etc.).

In one aspect, illustrated in FIGS. 3B and 3C, the cartridge 304 and theheating device 302 can be configured to operably interface with oneanother to provide and ensure proper heating of the biological sample.For example, the outer cover 324 can include at least one of a key or akeyway 358 that interfaces with a portion of the heating device 302, andthat is operable to facilitate proper alignment and/or orientation ofthe cartridge 304 with the heating device 302. Similarly, the heatingdevice 302 can include at least one of a key 368 or a keyway operable tofacilitate proper alignment of the enclosure 303 (e.g., provided by thecartridge 304) with the heating device 302. In the illustrated example,the heating device 302 can include a base 361 and a lid 362 rotatablycoupled to the base 361 (e.g., at a pivot or hinge 363). The key 368 canbe associated with at least one of the base 361 (as in this case) or thelid 362. In some examples, the heating device 302 can include a sensor316 associated with at least one of the base 361 or the lid 362 (as inthis case), which can be operable to determine whether the enclosure 303(e.g., the cartridge 304) is present in the heating device 302.

In one aspect, the enclosure interface 360 (and any associated heatsource 310 and/or related structures or devices) can be mounted or partof a floating platform to ensure a proper alignment and interface of theenclosure interface 360 with the cartridge 304 (e.g., the bottom wall355 a of the outer cover 324). For example, the enclosure interface 360and the heat source can be on or a part of a platform 364, which issuspended by one or more springs 365. In one aspect, the platform 364can serve as a heat spreader and the enclosure interface 360 can be asurface of the heat spreader. The springs 365 can deflect to accommodatethe presence of the cartridge 304, which can preload the springs 365 tomaintain the enclosure interface 360 and the cartridge 304 in contactwith one another to ensure effective conductive heat transfer from theenclosure interface 360 to the cartridge 304.

In one aspect, the heating device 302 can be configured to maintain thelid 362 in a closed position (e.g., as shown in FIGS. 3A and 4), whichcan ensure that the enclosure interface 360 and the cartridge 304 remainin contact with one another during the test. Any suitable structure ofdevice can be utilized for this purpose, such as a latch, a clasp, apin, etc. In one example, magnets 366 a, 366 b can be associated withthe base 361 and the lid 362, respectively. The magnets 366 a, 366 b canbe configured to provide a magnetic attraction force that exceeds theforce exerted by the springs 365 to maintain the lid 362 in a closedposition relative to the base 361.

The heating device 302 can include a power connection port 367 tofacilitate connection with a power cord (not shown) to receive powerfrom an external power source. In some examples, the heating device 302can be battery powered as an alternative or in addition to an externalpower source option. In some examples, the heating device 302 caninclude a battery that is operable to supply power for the heatingdevice 302.

In one aspect, as illustrated in FIG. 7, the heating device 302 can beconfigured to be coupled to other similar heating devices to provide fordistribution of power among several connected devices so that allconnected heating devices can run on a single power supply cable. Inthis case, each connected heating device 302 can include two powerconnection ports, and a power coupler 369 can be coupled betweenadjacent heating devices 302 to provide for power supply to eachconnected device. In this way, any suitable number of heating devices302 can be “ganged” together to facilitate performing multiple tests atthe same time. A compact configuration of the power coupler 369 canminimize the space occupied by the heating devise 302 and associatedelectrical couplings on a support surface (e.g., a table).

With reference to FIGS. 9A-9C, the chemical reaction pad 321 (FIG. 9B)can be supported by the tray 320. Top and side views of the chemicalreaction pad 321 are shown in FIGS. 13A and 13B, respectively. Ingeneral, the tray 320 can be of any suitable configuration to supportthe chemical reaction pad 321 while receiving a biological sample andundergoing a heating and cooling cycle to test the biological sample. Inone aspect, the tray 320 can include a bottom wall 330, end walls 331 a,331 b, and, in some examples, rails or guides 332 a, 332 b configured toform a receptacle or pocket 333 at a desired location on the tray 320and provide a boundary or barrier to confine the chemical reaction pad321 at that location. In the illustrated example, the chemical reactionpad 321 has a narrow or elongated “strip” configuration and the rails332 a, 332 b are spaced apart from one another to receive the chemicalreaction pad 321 between the rails 332 a, 332 b at a central location onthe tray 320 and prevent substantial movement of the chemical reactionpad 321 in that location. Although rails, guides, walls, etc. areillustrated for maintaining the chemical reaction pad 321 in a desiredlocation on the tray 320, it should be recognized that any structuresuitable for this purpose can be utilized, such as a spike (e.g., thatimpales the chemical reaction pad 321), a rounded or semisphericalprotrusion (e.g., that presses into or binds the chemical reaction pad321 with a locally high pressure), a column, a bar, or any othersuitable locating feature. It should also be recognized that the tray320 can be configured to position or orient the chemical reaction pad321 in any suitable position or orientation (e.g., rotated 90 degrees tothe orientation in the illustrated example). The tray 320 can be made ofany suitable material, such as a polymer (e.g., polypropylene,polycarbonate, polystyrene, polymethyl methacrylate (PMMA),polyethylene, etc.), glass, etc.

In one aspect, the chemical reaction pad 321 can have any suitableconfiguration. For example, as illustrated in FIG. 13B, top surfaces ofthe test sites 350 a-d can be raised or elevated above interveningstructures or spacers 351 a-c between the test sites 350 a-d, which canserve to separate the test sites 350 a-d from one another. As furtherillustrated in FIG. 13B, in some examples, the tops of the test sites350 a-d can each include a distribution or spreading layer 352 a-d,respectively, configured to facilitate spreading of liquid (e.g., abiological sample, such as a saliva sample) across the test sites 350a-d. In some examples, one or more test sites may not have adistribution layer.

In one aspect, as shown in a chemical reaction pad 321′ FIGS. 14A and14B, test sites 350 a‘-d’ can be at substantially the same level asintervening structures or spacers 351 a‘-c’ between the test sites 350a‘-d’. Although the test sites 350 a-d and 350 a‘-d’ are illustrated ashaving rectangular shapes, it should be recognized that a test site asdisclosed herein can have any suitable configuration, shape, orgeometry, such as a circular shape, a triangular shape, etc.

Furthermore, it should be recognized that a chemical reaction pad asdisclosed herein can have any suitable number of test sites. Forexample, a chemical reaction pad can have one test site (at 450 in FIG.15), two test sites (at 550 a, 550 b in FIG. 16), three test sites (at650 a-c in FIG. 17), four test sites (at 350 a-d in FIGS. 13A and 13B;at 350 a‘-d’ in FIGS. 14A and 14B; at 750 a-d in FIG. 18; at 850 a-d inFIG. 19), or more. In addition, test sites can be in any suitablearrangement relative to one another. For example, the test sites can bearranged linearly in a row (FIGS. 13A-14B, 16, and 17), in across-pattern (FIG. 18), in a grid pattern (FIG. 19), in a circularpattern, or any other suitable arrangement or pattern.

In one example, as illustrated in FIG. 20, a chemical reaction pad(e.g., a solid phase reaction medium) 921 for conducting a LAMP analysiscan comprise a substrate 953, an adhesive layer 959 disposed on thesubstrate 953, a reaction layer 973 including test sites, test spots,reaction locations, or segments 950 a-c, and spacers 951 a-d disposed onthe adhesive layer 959, and a spreading layer 952 disposed on thereaction layer 973. In one aspect, the test sites 950 a-c can include orotherwise hold reagents including one or more target primers, DNApolymerase, a re-solubilization agent, etc. In one aspect, the reagentscan form a composition sufficient to carry out a LAMP reaction.

The spreading layer 952 can facilitate a uniform spreading of abiological sample throughout different sections of the solid-phasereaction medium. In another example, the spreading layer can be lesshydrophilic than the solid-phase reaction medium. Having a spreadinglayer that is less hydrophilic than the solid-phase reaction medium canfacilitate the uniform spreading of the biological sample because thebiological sample will diffuse away from the less hydrophilic spreadinglayer towards the more hydrophilic solid-phase reaction medium.

In one aspect, the spacers 951 a-d can comprise one or more of glassfiber, nylon, cellulose, polysulfone, polyethersulfone, celluloseacetate, nitrocellulose, polystyrene, polyester, hydrophilicpolytetrafluoroethylene (PTFE), or combinations thereof. In anotheraspect, the spacers 951 a-d can be oriented in the same plane as thereaction layer 973 and oriented between segments of the reaction layer973.

The spatially discontinuous reaction layer 973 can allow multiplexing ofmultiple controls or multiple pathogens. For example, test site 950 acan be a positive control (e.g., test for a known saliva protein), testsite 950 b can be negative control (e.g., test for a colorimetric resultwithout including all of the reagents used for the LAMP reaction, andtest site or reaction segment 950 c can test for the target pathogen.

The spatially discontinuous test sites or reaction locations 950 a-c canalso allow for multiplexing of multiple pathogens. For example, testsite 950 a can test for influenza, test site 950 b can test for abacterial infection, and test site 950 c can test for a fungalinfection.

The dimensions of the reaction locations or segments 950 a-c can impactthe multiplexing potential. In one aspect, the test sites 950 a-c canhave a thickness from about 0.05 mm to about 2 mm. In another aspect,the test sites 950 a-c can have a width from about 4 mm to about 12 mmand a length from about 4 mm to about 25 mm. In one example, the testsites 950 a-c can be spatially discontinuous. In another example, thetest sites 950 a-c can have a surface area to thickness ratio from about90 to about 600.

In one example, the chemical reaction pad or solid-phase reaction medium921 can be configured to receive a biological fluid that can flowtransversely across the spreading layer 952 and that can migratevertically down into the test sites 950 a-c of the reaction layer 973.The test sites 950 a-c can contain all the components used for a RT-LAMPor LAMP reaction to occur. In one example, the test sites 950 a-c cancontain a re-solubilization agent (e.g., a surfactant), enzymes (e.g.,DNA polymerase, reverse transcriptase, DNase inhibitors, or RNaseinhibitors), stabilizers (e.g., blocking agents such as BSA or casein),a colorimetiic indicator (e.g., a magnesium colorimetric indicator, a pHcolorimetric indicator, or a DNA intercalating colorimetric indicator),and a buffer (e.g., 20 mM Tris).

The test sites 950 a-c can comprise any suitable material disclosedherein. In one example, the test sites 950 a-c can comprise one or moreof glass fiber, nylon, cellulose, polysulfone, polyethersulfone,cellulose acetate, nitrocellulose, hydrophilic PTFE, the like, orcombinations thereof. In one aspect, the pore size of the test sites 950a-c can be from about 1 to about 100 microns. The test sites 950 a-c canbe optically clean and smooth in appearance.

In another aspect, the test sites 950 a-c can provide a uniformend-color in a read zone for accurate and precise signal output ordetection. In one example, a biological sample can slowly migratevertically downward into the test sites 950 a-c. The end-color intensityof the test sites 950 a-c can be measured by a user with opticalobservation and comparison to a color chart or scale or with a handheldLED meter as percent reflectance units and converted to copies of RNA orDNA per reaction using a curve set calibrated against a laboratoryreference instrument, or as an optical image obtaining RGB values orpixel count which can be calibrated against a laboratory referenceinstrument. The concentration of RNA or DNA can be determined by theend-color intensity at a selected time or by kinetic rate determination.

As shown in FIG. 10, the chemical reaction pad cover 322 can be disposedover the chemical reaction pad 321 (hidden from view in FIG. 10). FIGS.11A and 11B show top and bottom isometric views, respectively, of thechemical reaction pad cover 322 isolated from other components of thecartridge 304. The chemical reaction pad cover 322 can have a sampleopening 323 to facilitate depositing a liquid biological sample at apredetermined location on the chemical reaction pad 321 to ensure thatbiological samples are consistently and properly deposited for each testperformed by a variety of different users. For example, the chemicalreaction pad cover 322 can include a top portion 340 configured toextend substantially over the chemical reaction pad 321. The sampleopening 323 can be formed at a suitable (e.g., central) location in thetop portion 340 to facilitate depositing a liquid biological sample onthe chemical reaction pad 321 below the top portion 340. The sampleopening 323 can have any suitable shape, geometry, or configuration(e.g., a rectangle shape, a circular shape, a slot configuration, afunnel configuration, etc.) to facilitate depositing a liquid biologicalsample at a predetermined location on the chemical reaction pad 321. Insome examples, only a single sample opening may be included. In otherexamples, multiple sample openings can be included, which can allowdepositing a liquid biological sample at multiple locations on thechemical reaction pad 321. In the illustrated example, the chemicalreaction pad 321 includes multiple (e.g., four) test sites 350 a-d.Thus, in one example, the chemical reaction pad cover 322 can include asample opening corresponding to each of the four test sites 350 a-d. Insuch cases, the chemical reaction pad cover 322 may not include acapillary channel as such a channel may not be needed to adequatelydistribute a liquid biological sample across the chemical reaction padto the various test sites 350 a-d.

In one aspect, shown in FIGS. 10 and 11A, the chemical reaction padcover 322 can include indicia 341 configured to indicate to a user thelocation of the sample opening 323. Any suitable type of indicia can beutilized, such as shapes (e.g., an arrow, a triangle, a circle, a line,etc.), alphanumeric characters, a combination of these, etc. The indicia341 can be of any suitable type or construction, such as formed into oron the chemical reaction pad cover 322 (e.g., embossed, molded, stamped,etc. into or on the top portion 340), printed on the chemical reactionpad cover 322, etc.

As shown in FIG. 11B, the chemical reaction pad cover 322 can include acapillary channel 342 in fluid communication with the sample opening 323to distribute a liquid biological sample across or along the chemicalreaction pad 321 (e.g., to one or more of the various test sites 350a-d). The capillary channel 342 can have any suitable cross-sectionalshape or configuration known in the art for conveying a liquid along anunderside of the chemical reaction pad cover 322 via capillary actionand/or surface tension, such as a U-shape (FIG. 21A), a V-shape (FIG.21B), a T-shape (FIG. 21C), etc.

In one aspect, the capillary channel 342 can have any suitable patternor path shape, such as at least one of a linear configuration, across-configuration, or an X configuration, a circular or curvedconfiguration, which may be configured based on the pattern,distribution, or location of the underlying test sites. For example, thechemical reaction pad 321 as illustrated has a strip configuration withlinearly arranged test sites 350 a-d. In this case, the capillarychannel 342 can have a linear configuration to facilitate delivery of abiological sample to one or more of the various test sites 350 a-d. Alinear capillary channel configuration of capillary channels 542, 642can also be utilized with the linear arrangement of test sites in thechemical reaction pad examples shown in FIGS. 16 and 17, respectively. Acapillary channel 742 having a cross-configuration can be utilized todeliver a biological sample to one or more of the various test sites ofthe chemical reaction pad example shown in FIG. 18, which are arrangedin a cross pattern or configuration. A capillary channel 842 having an Xconfiguration can be utilized to deliver a biological sample to one ormore of the various test sites of the chemical reaction pad exampleshown in FIG. 19, which are arranged in a grid pattern or configuration.A capillary channel with an X configuration may also be suitable for usewith a wide chemical reaction pad in a strip configuration with linearlyarranged test sites.

Although various capillary channels are discussed herein, it should berecognized that a chemical reaction pad cover in accordance with thepresent disclosure need not include a capillary channel, as a liquidbiological sample may be adequately distributed across the chemicalreaction pad in some examples without relying on a capillary channel.For example, a chemical reaction pad and/or a chemical reaction padcover may be configured to facilitate distribution of a liquidbiological sample across the chemical reaction pad even without the aidof a capillary channel (e.g., a chemical reaction pad may have adistribution layer or other such material or layer, test sites may bearranged in close proximity to a sample opening in the chemical reactionpad cover, a sample opening may be associated with each test site,etc.).

In one aspect, the chemical reaction pad cover 322 can include a bottomsurface 343 (FIG. 11B) configured to form a top wall or barrier over thereceptacle or pocket 333 of the tray 320 (FIG. 9A) to maintain thechemical reaction pad 321 between the rails 332 a, 332 b and preventsubstantial movement of the chemical reaction pad 321 in that location.In some examples, the bottom surface 343 can be sized to fit between therails 332 a, 332 b. In other examples, the bottom surface 343 can beconfigured to fit over the rails 332 a, 332 b.

In one aspect, the chemical reaction pad cover 322 can be coupled to thetray 320. For example, the tray 320 can include coupling features 334(e.g., resiliently flexible coupling protrusions) and the chemicalreaction pad cover 322 can include mating coupling features 344 (e.g.,coupling recesses) configured to engage one another to mechanicallysecure the chemical reaction pad cover 322 to the tray 320 in a fixedrelationship to properly locate the sample opening 323 and/or thecapillary channel 342 over a predetermined location of the chemicalreaction pad 321 (e.g., in a middle portion of the pad 321 and/or overone or more test sites 350 a-d). The coupling features 334 can have anysuitable configuration and can be at any suitable location, such asassociated with one or more outer walls 335 a, 335 b of the tray 320.Similarly, the coupling features 344 can have any suitable configurationand can be at any suitable location, such as associated with one or moreouter walls 345 a, 345 b of the chemical reaction pad cover 322.

In one aspect, the cartridge 304 can include a handle 325 (FIGS. 8A-10)coupled to the tray 320 to facilitate grasping the cartridge 304 by auser. The handle 325 can be made of any suitable material, such as anelastomer (e.g., thermoplastic elastomer (TPE), thermoplasticpolyurethane (TPU), silicone, nitrile butadiene rubber (Buna-N),styrene-butadiene rubber (SBR), ethylene propylene diene monomer (EPDM),etc.). In some examples, the cartridge 304 can include a tray base 326(FIGS. 9A-10) coupled to the tray 320. The tray base 326 can provide astructural interface for coupling with the outer cover 324. The traybase 326 can also provide a structural support for the handle 325, whichcan be coupled to the tray base 326.

In some examples, the tray base 326 can be coupled to the tray 320 via areduced cross-sectional area portion 336 to reduce or minimizeconductive heat transfer from the tray 320 to the handle 325, which canprevent burns or discomfort of the user when handling the cartridge 304immediately following a test of a biological sample (e.g., when removingthe cartridge 304 from the heating device 302 for interpretation of thetest results). The reduced cross-sectional area portion 336 can have anysuitable configuration that reduces cross-sectional area between thetray 320 and the tray base 326. For example, the reduced cross-sectionalarea portion 336 can include beams 337 a, 337 b that extend between thetray 320 and the tray base 326 and leave an open space 338 between thetray 320 and the tray base 326. Thus, the open space 338 can providethermal insulation and limit heat transfer between the tray 320 and thetray base 326, with a conductive heat transfer path from the tray 320 tothe tray base 326 being through the beams 337 a, 337 b. The beams 337 a,337 b can be configured to provide adequate structural support betweenthe tray 320 and the tray base 326 in the absence of material in thelocation that forms the open space 338.

The outer cover 324 can define an opening or chamber 354 (FIG. 12B) toreceive the chemical reaction pad 322 (and associated structures, suchas the tray 320 and the chemical reaction pad cover 322). For example,the chamber 354 can be defined at least in part by one or more walls 355a-e (FIGS. 8A, 8B, 12A, and 12B). An entrance to the chamber 354 can bedefined by a tray base interface portion 356 configured to interfacewith the tray base 326. For example, interior surfaces 357 a, 357 b(FIG. 12B) of the tray base interface portion 356 can be configured tointerface with the tray base 326. The tray base 326 can a rim or flange339 to provide a backing interface surface for the tray base interfaceportion 356 with the tray base 326.

In one aspect, the outer cover 324 can be operable to at least partiallyform the enclosure 303 (FIGS. 8A and 8B) about the chemical reaction pad322 (and associated structures, such as the tray 320 and the chemicalreaction pad cover 322). In one aspect, the cartridge 304 can includeone or more seals 327 a, 327 b (FIGS. 9A-10) operable with the outercover 324 to seal the enclosure 303 about the chemical reaction pad 322.In another aspect, the tray base 326 can be configured to interface withthe outer cover 324 to form the enclosure 303 about the chemicalreaction pad 322. Thus, in some examples, the tray base 326 can includeand/or support the seals 327 a, 327 b. The seals 327 a, 327 b can beconfigured to maintain a seal about biological sample material withinthe enclosure 303 to ensure test integrity by preventing externalmaterial (e.g., from a previous test) from contaminating the biologicalsample within the enclosure 303, as well as maintaining an environmentwithin the enclosure 303 that prevents the biological material fromdrying out during the test. The seals 327 a, 327 b can also assist inmaintaining the integrity of subsequent tests performed on the sameheating device 302 by preventing biological material from escaping andcontaminating the heating device 302. In addition, the seals 327 a, 327b can maintain safety by ensuring that no biological sample material canescape and pose a health risk to the user or others. Thus, in someexamples, the seals 327 a, 327 b can be configured to provide a hermeticseal. The cartridge 304 can therefore be self-contained and sealed sothat the heating device 302 cannot be contaminated. This can simplifythe design of the heating device 302 because the heating device 302 doesnot need to be configured to capture or contain the biological sample(e.g., contaminants) or be configured for ease of cleaning.

In the illustrated example, the seals 327 a, 327 b can be configured tointerface with the interior surfaces 357 a, 357 b, respectively, of thetray base interface portion 356 of the outer cover 324. In one aspect,the sealing perimeter at this interface can be minimized in order tominimize the area where leakage can occur. Although two seals 327 a, 327b are shown in the illustrated example, it should be recognized that anysuitable number of seals can be utilized (e.g., only a single seal ormore than two seals). Utilizing multiple seals (e.g., two seals) canprovide redundancy. Because the biological sample is heated by theheating device 302 in order to perform a test of the biological sample,the increase in temperature can elevate the pressure inside theenclosure 303. Therefore, in one aspect, the air volume inside theenclosure 303 can be minimized or reduced to a level that can be safelysealed by the seals 327 a, 327 b throughout the heating cycle of thetest procedure.

The seals 327 a, 327 b can include any suitable material, such as anelastomer (e.g., thermoplastic elastomer (TPE), thermoplasticpolyurethane (TPU), silicone, nitrile butadiene rubber (Buna-N),styrene-butadiene rubber (SBR), ethylene propylene diene monomer (EPDM),etc.). In one aspect, the seal material can be selected so as to be hardenough to allow suitable compression to form an effective seal, but nottoo soft such that a proper seal cannot be maintained under the designconditions. In some examples, the seal material can have a hardness ofabout 30-60 Shore A durometer. In some examples, the seals 327 a, 327 band the handle 325 can be made of the same material. The seals 327 a,327 b can have any suitable configuration, such as a gasket, an O-ring,etc. In one aspect, the seals 327 a, 327 b can be attached and/orintegrally formed with the underlying structure. For example, the seals327 a, 327 b and the associated tray base 326 structure can bepermanently attached and/or integrally formed with one another. In someexamples, the seals 327 a, 327 b and the handle 325 can be integrallyformed of a single, unitary component or structure. In cases where theseals 327 a, 327 b are attached and/or integrally formed with theunderlying structure, the seals 327 a, 327 b can be overmolded on theunderlying structure, which can molecularly bond the seals to theunderlying structure thereby enhancing the integrity and robustness ofthe seals. For example, elastomer seals 327 a, 327 b can be overmoldedonto an underlying polymer (e.g., polypropylene) structure, such as thatused to form the tray 320 and a structural frame underlying the traybase 326 and the handle 325.

In one aspect, the cartridge 304 can include a latch 328 (FIG. 8A)operable to facilitate latching the outer cover 324 to the tray base326. For example, the outer cover 324 can include a first latch portion329 a (e.g., a tab or other suitable protrusion as shown in FIGS. 8A,12A, and 12B) and a second latch portion 329 b (e.g., a catch defining asuitable recess as shown in FIGS. 8A, 9A, 9B, and 10) can be associatedwith the tray base 326. The first and second latch portions 329 a, 329 bcan interface with and engage one another to secure the outer cover 324to the tray base 326. In one aspect, the latch 328 can maintain theseals 327 a, 327 b in a preloaded condition to ensure a proper sealbetween the outer cover 324 the tray base 326.

The chemical reaction pad cover 322 and the outer cover 324 can be madeof any suitable material, such as a polymer (e.g., polypropylene,polycarbonate, polystyrene, polymethyl methacrylate (PMMA),polyethylene, etc.), glass, etc. In one aspect, at least one of thechemical reaction pad cover 322 or the outer cover 324 can be at leastpartially optically transparent or translucent to facilitate opticalinspection of the chemical reaction pad 321 to determine a test result.In some examples, substantially the entire chemical reaction pad cover322 and/or outer cover 324 can be constructed of optically transparentor translucent material.

In use, an operator can apply the liquid biological sample 301 to thechemical reaction pad 321, for example, by depositing the biologicalsample 301 into the sample opening 323. The tray 320 and the chemicalreaction pad 321 are shown in FIG. 22 with the chemical reaction padcover 222 omitted for clarity. The biological sample 301 can then spreadacross the chemical reaction pad 321 to the various test sites 350 a-d,which can be aided by a spreading layer and/or the capillary channel 342in the chemical reaction pad cover 222. The outer cover 324 can then beplaced over the tray 320, the chemical reaction pad 321, and thechemical reaction pad cover 222 to fully assemble the cartridge 304, asshown in FIGS. 8A and 8B. With the fully assembled cartridge 304containing the biological sample 301, the cartridge 304 can then beplaced into the heating device 302 as shown in FIG. 3B, and then the lid362 can be closed over the cartridge 304 against the base 361, as shownin FIG. 3A. A test can be initiated by activating the heating device302. At the end of the test, the lid 362 can be opened and the testcartridge 304 can be removed. The chemical reaction pad 321 can bevisually inspected to determine the results of the test (e.g., asindicated by the color of one or more of the test sites 350 a-d), asillustrated in FIG. 23.

In some examples, as illustrated in FIG. 23, the test sites 350 a-d canbe visible through the chemical reaction pad cover 222 and the outercover 324 to facilitate visual inspection of the test sites 350 a-dwithout the need to remove the covers 324, 322. In one example, thechemical reaction pad cover 322 and/or the outer cover 324 can be atleast partially optically transparent or translucent. In anotherexample, at least one of the chemical reaction pad cover 322 or theouter cover 324 can include one or more optically transparent ortranslucent windows 346 to facilitate optical inspection of theunderlying chemical reaction pad 321 (e.g., located over the test sites350 a-d).

FIG. 24 illustrates a liquid biological sample test cartridge 1004 inaccordance with another example of the present disclosure. As with othercartridges disclosed herein, the cartridge 1004 can include a tray 1020,a chemical reaction pad (hidden from view) supported by the tray 1020,and a chemical reaction pad cover 1022 disposed over the chemicalreaction pad.

The chemical reaction pad cover 1022 can be coupled to the tray 1020.The chemical reaction pad cover 1022 can have a sample opening 1023 tofacilitate depositing a liquid biological sample at a predeterminedlocation on the chemical reaction pad. In addition, the cartridge 1004can include an outer cover 1024 operable to at least partially form anenclosure about the chemical reaction pad.

In the FIG. 24 example, the outer cover 1024 and the tray 1020 can formthe enclosure about the chemical reaction pad. For example, the tray1020 can be configured as a container and the outer cover 1024 can beconfigured as a lid over the container. In some examples, the outercover 1024 can be pivotally coupled to the tray 1020 (e.g., by a livinghinge). In one aspect, the cartridge 1004 can include a seal 1027operable with the tray 1020 and the outer cover 1024 to seal theenclosure about the chemical reaction pad. One or more latches 1028 a-ccan be included to secure the outer cover 1024 and the tray 1020 to oneanother and maintain the enclosure seal.

In one aspect, as illustrated in FIG. 25, a liquid biological sampletest kit 1105 can comprise a pouch 1106 and a liquid biological sampletest cartridge 1104 as disclosed herein sealed within the pouch 1106.The cartridge 1104 may or may not be in a fully assembled conditionwithin the pouch 1106 (e.g., an outer cover may be separate or uncoupledfrom other components of the cartridge 1104).

In accordance with one aspect of the present disclosure, a tangible andnon-transitory computer readable medium can comprise one or morecomputer software modules configured to direct one or more processors toreceive temperature data generated by a thermal sensor, the temperaturedata associated with a biological sample, determine a control commandfor a heat source based on the temperature data, the heat source beingoperable to heat the biological sample, wherein the control command isconfigured to heat the biological sample at less than or equal to about2 degrees C./s, and communicate the control command to the heat source.

In one aspect, the control command can be configured to control heatgeneration by the heat source to heat the biological sample from about0.5-1.5 degrees C./s. In another aspect, the control command can beconfigured to control heat generation by the heat source to heat thebiological sample from about 0.8-1.2 degrees C./s.

In one aspect, the tangible and non-transitory computer readable mediumcan comprise one or more computer software modules configured to directone or more processors to receive time data generated by a timer,determine an expiration of a predetermined incubation time interval forthe biological sample beginning when the temperature data indicates atemperature value greater than or equal to a predetermined minimumtemperature value, and communicate a termination command to the heatsource to cease heat generation upon expiration of the incubationperiod.

In accordance with one embodiment of the present invention, a method forfacilitating testing of a liquid biological sample is disclosed. Themethod can comprise supporting a chemical reaction pad with a tray. Themethod can also comprise disposing a chemical reaction pad cover overthe chemical reaction pad and coupling the chemical reaction pad coverto the tray. The method can further comprise facilitating depositing aliquid biological sample at a predetermined location on the chemicalreaction pad. Additionally, the method can comprise providing an outercover operable to at least partially form an enclosure about thechemical reaction pad. It is noted that no specific order is required inthis method, though generally in one embodiment, these method steps canbe carried out sequentially.

In one aspect of the method, facilitating depositing a liquid biologicalsample at a predetermined location on the chemical reaction pad cancomprise providing a sample opening in the chemical reaction pad cover.

In one aspect of the method, facilitating depositing a liquid biologicalsample at a predetermined location on the chemical reaction pad canfurther comprise providing a capillary channel in fluid communicationwith the sample opening to distribute the liquid biological sample alongthe chemical reaction pad.

In one aspect, the method can further comprise facilitating sealing theenclosure about the chemical reaction pad. In one aspect, facilitatingsealing the enclosure about the chemical reaction pad can compriseproviding a seal operable with the outer cover.

In accordance with one embodiment of the present invention, a method forfacilitating testing of a liquid biological sample can comprisefacilitating heating of a biological sample at less than or equal toabout 2 degrees C./s. In one aspect of the method, facilitating heatingof the biological sample can comprise obtaining a controller incommunication with a heat source, the controller being operable tocontrol heat generation by the heat source. In one aspect, the methodcan further comprise obtaining a thermal sensor in communication withthe controller, the thermal sensor being operable to sense a temperatureassociated with the biological sample, wherein the controller controlsheat generation by the heat source based on the temperature. In oneaspect, the method can further comprise facilitating termination ofheating the biological sample upon expiration of a predeterminedincubation time period. In one aspect, facilitating termination ofheating the biological sample upon expiration of a predeterminedincubation time period can comprise obtaining a timer in communicationwith the controller and operable to provide time data to the controller,wherein the controller controls the heater to provide heat for thepredetermined incubation time period. It is noted that no specific orderis required in this method, though generally in one embodiment, thesemethod steps can be carried out sequentially.

Reference was made to the examples illustrated in the drawings andspecific language was used herein to describe the same. It willnevertheless be understood that no limitation of the scope of thetechnology is thereby intended. Alterations and further modifications ofthe features illustrated herein and additional applications of theexamples as illustrated herein are to be considered within the scope ofthe description.

Although the disclosure may not expressly disclose that some embodimentsor features described herein may be combined with other embodiments orfeatures described herein, this disclosure should be read to describeany such combinations that would be practicable by one of ordinary skillin the art. The user of “or” in this disclosure should be understood tomean non-exclusive or, i.e., “and/or,” unless otherwise indicatedherein.

Furthermore, the described features, structures, or characteristics maybe combined in any suitable manner in one or more examples. In thepreceding description, numerous specific details were provided, such asexamples of various configurations to provide a thorough understandingof examples of the described technology. It will be recognized, however,that the technology may be practiced without one or more of the specificdetails, or with other methods, components, devices, etc. In otherinstances, well-known structures or operations are not shown ordescribed in detail to avoid obscuring aspects of the technology.

Although the subject matter has been described in language specific tostructural features and/or operations, it is to be understood that thesubject matter defined in the appended claims is not necessarily limitedto the specific features and operations described above. Rather, thespecific features and acts described above are disclosed as exampleforms of implementing the claims.

Numerous modifications and alternative arrangements may be devisedwithout departing from the spirit and scope of the described technology.

What is claimed is:
 1. A heating device for testing a biological sample,comprising: a heat source operable to generate heat; and a controller incommunication with the heat source and operable to control heatgeneration by the heat source to heat a biological sample at less thanor equal to about 2 degrees C./s.
 2. The heating device of claim 1,wherein the controller is operable to control heat generation by theheat source to heat the biological sample from about 0.5-1.5 degreesC./s.
 3. The heating device of claim 2, wherein the controller isoperable to control heat generation by the heat source to heat thebiological sample from about 0.8-1.2 degrees C./s.
 4. The heating deviceof claim 1, further comprising a timer in communication with thecontroller and operable to provide time data to the controller, whereinthe controller controls the heater to provide heat for a predeterminedincubation time period.
 5. The heating device of claim 1, furthercomprising a thermal sensor in communication with the controller, thethermal sensor being operable to sense a temperature associated with thebiological sample, wherein the controller controls heat generation bythe heat source based on the temperature.
 6. The heating device of claim5, wherein the thermal sensor comprises at least one of a contact sensoror a non-contact sensor.
 7. The heating device of claim 5, wherein thethermal sensor comprises at least one of an optical thermal sensor, aninfrared thermal sensor, a thermocouple, a thermistor, or a resistancetemperature detector (RTD).
 8. The heating device of claim 1, whereinthe heat source comprises at least one of a resistance heater, aninduction heater, a radiant heater, a convection heater, athermoelectric heater, or a heat spreader.
 9. The heating device ofclaim 1, further comprising a thermal sensor in communication with thecontroller, the thermal sensor being operable to sense a temperatureassociated with the heat source.
 10. The heating device of claim 1,wherein the biological sample is at least partially contained within anenclosure, and the heat source is configured to interface with theenclosure such that heat is transferred from the heat source to theenclosure by conduction.
 11. The heating device of claim 1, furthercomprising a chamber configured to receive the biological sampletherein.
 12. The heating device of claim 11, wherein the chamber isdefined at least in part by a portion of the heat source.
 13. Theheating device of claim 11, wherein the heat source is physicallyseparated from the biological sample such that heat is transferred fromthe heat source to the biological sample by at least one of radiation orconvection.
 14. The heating device of claim 13, wherein the biologicalsample is at least partially contained within an enclosure and heat istransferred from the heat source to the enclosure by at least one ofradiation or convection.
 15. A heating device for testing a biologicalsample, comprising: a heat source operable to generate heat to heat abiological sample, the biological sample being at least partiallycontained within a removable enclosure distinct from the heating device;and an enclosure interface associated with the heat source, wherein theenclosure interface is configured to interface with the enclosure suchthat heat is transferred from the heat source to the enclosure byconduction.
 16. The heating device of claim 15, further comprising acontroller in communication with the heat source and operable to controlheat generation by the heat source to heat a biological sample at lessthan or equal to about 2 degrees C./s.
 17. The heating device of claim16, wherein the controller is operable to control heat generation by theheat source to heat the biological sample from about 0.5-1.5 degreesC./s.
 18. The heating device of claim 17, wherein the controller isoperable to control heat generation by the heat source to heat thebiological sample from about 0.8-1.2 degrees C./s.
 19. The heatingdevice of claim 17, further comprising a timer in communication with thecontroller and operable to provide time data to the controller, whereinthe controller controls the heater to provide heat for a predeterminedincubation time period.
 20. The heating device of claim 16, furthercomprising a thermal sensor in communication with the controller, thethermal sensor being operable to sense a temperature associated with thebiological sample, wherein the controller controls heat generation bythe heat source based on the temperature.
 21. The heating device ofclaim 20, wherein the temperature associated with the biological sampleis a temperature of at least a portion of the enclosure.
 22. The heatingdevice of claim 20, wherein the thermal sensor comprises at least one ofa contact sensor or a non-contact sensor.
 23. The heating device ofclaim 20, wherein the thermal sensor comprises at least one of anoptical thermal sensor, an infrared thermal sensor, a thermocouple, athermistor, or a resistance temperature detector (RTD).
 24. The heatingdevice of claim 15, wherein the heat source comprises at least one of aresistance heater, an induction heater, a radiant heater, a convectionheater, a thermoelectric heater, or a heat spreader.
 25. The heatingdevice of claim 15, further comprising a thermal sensor in communicationwith the controller, the thermal sensor being operable to sense atemperature associated with the heat source.
 26. The heating device ofclaim 15, further comprising a base and a lid rotatably coupled to thebase.
 27. The heating device of claim 26, further comprising a sensorassociated with at least one of the base or the lid, the sensor beingoperable to determine whether the enclosure is present.
 28. The heatingdevice of claim 26, further comprising at least one of a key or a keywayassociated with at least one of the base or the lid, the at least one ofthe key or the keyway being operable to facilitate proper alignment ofthe enclosure with the at least one of the base or the lid.
 29. Atangible and non-transitory computer readable medium comprising one ormore computer software modules configured to direct one or moreprocessors to: receive temperature data generated by a thermal sensor,the temperature data associated with a biological sample; determine acontrol command for a heat source based on the temperature data, theheat source being operable to heat the biological sample, wherein thecontrol command is configured to heat the biological sample at less thanor equal to about 2 degrees C./s; and communicate the control command tothe heat source.
 30. The tangible and non-transitory computer readablemedium of claim 29, wherein the control command is configured to controlheat generation by the heat source to heat the biological sample fromabout 0.5-1.5 degrees C./s.
 31. The tangible and non-transitory computerreadable medium of claim 30, wherein the control command is configuredto control heat generation by the heat source to heat the biologicalsample from about 0.8-1.2 degrees C./s.
 32. The tangible andnon-transitory computer readable medium of claim 29, further comprising:receive time data generated by a timer; determine an expiration of apredetermined incubation time interval for the biological samplebeginning when the temperature data indicates a temperature valuegreater than or equal to a predetermined minimum temperature value; andcommunicate a termination command to the heat source to cease heatgeneration upon expiration of the incubation period.
 33. A method forfacilitating testing of a liquid biological sample, comprising:facilitating heating of a biological sample at less than or equal toabout 2 degrees C./s.
 34. The method of claim 33, wherein facilitatingheating of the biological sample comprises obtaining a controller incommunication with a heat source, the controller being operable tocontrol heat generation by the heat source.
 35. The method of claim 34,further comprising obtaining a thermal sensor in communication with thecontroller, the thermal sensor being operable to sense a temperatureassociated with the biological sample, wherein the controller controlsheat generation by the heat source based on the temperature.
 36. Themethod of claim 34, further comprising facilitating termination ofheating the biological sample upon expiration of a predeterminedincubation time period.
 37. The method of claim 36, wherein facilitatingtermination of heating the biological sample upon expiration of apredetermined incubation time period comprises obtaining a timer incommunication with the controller and operable to provide time data tothe controller, wherein the controller controls the heater to provideheat for the predetermined incubation time period.